tbuckley/cabot-search huggingface dataset:
Expressed Barcoding Enables High-Resolution Tracking of the Evolution of Drug Tolerance
Authors: Jennifer L. Cotton, Javier Estrada Diez, Vivek Sagar, Julie Chen, Michelle Piquet, John Alford, Youngchul Song, Xiaoyan Li, Markus Riester, Matthew T. DiMare, Katja Schumacher, Gaylor Boulay, Kathleen Sprouffske, Lin Fan, Tyler Burks, Leandra Mansur, Joel Wagner, Hyo-eun C. Bhang, Oleg Iartchouk, John Reece-Hoyes, Erick J. Morris, Peter S. Hammerman, David A. Ruddy, Joshua M. Korn, Jeffrey A. Engelman, Matthew J. Niederst
Journal: Cancer Research (2023)

Abstract For a majority of patients with non–small cell lung cancer with EGFR mutations, treatment with EGFR inhibitors (EGFRi) induces a clinical response. Despite this initial reduction in tumor size, residual disease persists that leads to disease relapse. Elucidating the preexisting biological differences between sensitive cells and surviving drug-tolerant persister cells and deciphering how drug-tolerant cells evolve in response to treatment could help identify strategies to improve the efficacy of EGFRi. In this study, we tracked the origins and clonal evolution of drug-tolerant cells at a high resolution by using an expressed barcoding system coupled with single-cell RNA sequencing. This platform enabled longitudinal profiling of gene expression and drug sensitivity in response to EGFRi across a large number of clones. Drug-tolerant cells had higher expression of key survival pathways such as YAP and EMT at baseline and could also differentially adapt their gene expression following EGFRi treatment compared with sensitive cells. In addition, drug combinations targeting common downstream components (MAPK) or orthogonal factors (chemotherapy) showed greater efficacy than EGFRi alone, which is attributable to broader targeting of the heterogeneous EGFRi-tolerance mechanisms present in tumors. Overall, this approach facilitates thorough examination of clonal evolution in response to therapy that could inform the development of improved diagnostic approaches and treatment strategies for targeting drug-tolerant cells. Significance: The evolution and heterogeneity of EGFR inhibitor tolerance are identified in a large number of clones at enhanced cellular and temporal resolution using an expressed barcode technology coupled with single-cell RNA sequencing.
Selection and Interpretation of Molecular Diagnostics in Heart Transplantation
Authors: Jason F. Goldberg, Lauren K. Truby, Sean Agbor-Enoh, Annette M. Jackson, Christopher R. deFilippi, Kiran K. Khush, Palak Shah
Journal: Circulation (2023)

The number of heart transplants performed annually in the United States and worldwide continues to increase, but there has been little change in graft longevity and patient survival over the past 2 decades. The reference standard for diagnosis of acute cellular and antibody-mediated rejection includes histologic and immunofluorescence evaluation of endomyocardial biopsy samples, despite invasiveness and high interrater variability for grading histologic rejection. Circulating biomarkers and molecular diagnostics have shown substantial predictive value in rejection monitoring, and emerging data support their use in diagnosing other posttransplant complications. The use of genomic (cell-free DNA), transcriptomic (mRNA and microRNA profiling), and proteomic (protein expression quantitation) methodologies in diagnosis of these posttransplant outcomes has been evaluated with varying levels of evidence. In parallel, growing knowledge about the genetically mediated immune response leading to rejection (immunogenetics) has enhanced understanding of antibody-mediated rejection, associated graft dysfunction, and death. Antibodies to donor human leukocyte antigens and the technology available to evaluate these antibodies continues to evolve. This review aims to provide an overview of biomarker and immunologic tests used to diagnose posttransplant complications. This includes a discussion of pediatric heart transplantation and the disparate rates of rejection and death experienced by Black patients receiving a heart transplant. This review describes diagnostic modalities that are available and used after transplant and the landscape of future investigations needed to enhance patient outcomes after heart transplantation.
Glasdegib plus intensive or non-intensive chemotherapy for untreated acute myeloid leukemia: results from the randomized, phase 3 BRIGHT AML 1019 trial
Authors: Mikkael A. Sekeres, Pau Montesinos, Jan Novak, Jianxiang Wang, Deepa Jeyakumar, Benjamin Tomlinson, Jiri Mayer, Erin Jou, Tadeusz Robak, David C. Taussig, Hervé Dombret, Akil Merchant, Naveed Shaik, Thomas O’Brien, Whijae Roh, Xueli Liu, Wendy Ma, Christine G. DiRienzo, Geoffrey Chan, Jorge E. Cortes
Journal: Leukemia (2023)

This is the primary report of the randomized, placebo-controlled phase 3 BRIGHT AML 1019 clinical trial of glasdegib in combination with intensive chemotherapy (cytarabine and daunorubicin) or non-intensive chemotherapy (azacitidine) in patients with untreated acute myeloid leukemia. Overall survival (primary endpoint) was similar between the glasdegib and placebo arms in the intensive (n = 404; hazard ratio [HR] 1.05; 95% confidence interval [CI]: 0.782-1.408; two-sided p = 0.749) and non-intensive (n = 325; HR 0.99; 95% CI: 0.768-1.289; two-sided p = 0.969) studies. The proportion of patients who experienced treatment-emergent adverse events was similar for glasdegib versus placebo (intensive: 99.0% vs. 98.5%; non-intensive: 99.4% vs. 98.8%). The most common treatment-emergent adverse events were nausea, febrile neutropenia, and anemia in the intensive study and anemia, constipation, and nausea in the non-intensive study. The addition of glasdegib to either cytarabine and daunorubicin or azacitidine did not significantly improve overall survival and the primary efficacy endpoint for the BRIGHT AML 1019 phase 3 trial was not met. Clinical trial registration: ClinicalTrials.gov: NCT03416179.
Ethanol-Induced Atrial Fibrillation Results From Late <i>I</i> <sub>Na</sub> and Can Be Prevented by Ranolazine
Authors: Julian Mustroph, Maria J. Baier, Denise Unsin, Zdenek Provaznik, Kostiantyn Kozakov, Simon Lebek, Daniel Tarnowski, Sönke Schildt, Niels Voigt, Stefan Wagner, Lars S. Maier, Stefan Neef
Journal: Circulation (2023)
Cardiorenal Biomarkers, Canagliflozin, and Outcomes in Diabetic Kidney Disease: The CREDENCE Trial
Authors: James L. Januzzi, Reza Mohebi, Yuxi Liu, Naveed Sattar, Hiddo J.L. Heerspink, Eshetu Tefera, Muthiah Vaduganathan, Javed Butler, Yshai Yavin, Jingwei Li, Carol A. Pollock, Vlado Perkovic, Bruce Neal, Michael K. Hansen
Journal: Circulation (2023)

BACKGROUND: People with type 2 diabetes and albuminuria are at an elevated risk for cardiac and renal events. The optimal biomarkers to aid disease prediction and to understand the benefits of sodium-glucose cotransporter-2 inhibition remain unclear. METHODS: Among 2627 study participants in the CREDENCE trial (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), concentrations of NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T, growth differentiation factor-15, and IGFBP7 (insulin-like growth factor binding protein 7) were measured. The effect of canagliflozin on biomarker concentrations was evaluated. The prognostic potential of each biomarker on the primary outcome (a composite of end-stage kidney disease [dialysis, transplantation, or a sustained estimated glomerular filtration rate of &lt;15 mL·min −1 ·1.73 m −2 ], doubling of the serum creatinine level, or renal death or cardiovascular death) was assessed. RESULTS: The median (quartiles 1 and 3) concentration of each biomarker was generally elevated: NT-proBNP, 180 ng/L (82, 442 ng/L); high-sensitivity cardiac troponin T, 19 ng/L (12, 29 ng/L); growth differentiation factor-15, 2595 ng/L (1852, 3775 ng/L); and IGFBP7, 121.8 ng/mL (105.4, 141.5 ng/mL). At 1 year, the biomarkers all rose by 6% to 29% in the placebo arm but only by 3% to 10% in the canagliflozin arm (all P &lt;0.01 in multivariable linear mixed-effect models). Baseline concentrations of each biomarker were strongly predictive of cardiac and renal outcomes. When the biomarkers were analyzed together in a multimarker panel, individuals with high risk scores (hazard ratio [HR], 4.01 [95% CI, 2.52–6.35]) and moderate risk scores (HR, 2.39 [95% CI, 1.48–3.87]) showed a higher risk for the primary outcome compared with those with low risk scores. By 1 year, a 50% increase in NT-proBNP (HR, 1.11 [95% CI, 1.08–1.15]), high-sensitivity cardiac troponin T (HR, 1.86 [95% CI, 1.64–2.10]), growth differentiation factor-15 (HR, 1.45 [95% CI, 1.24–1.70]), and IGFBP7 (HR, 3.76 [95% CI, 2.54–5.56]) was associated with risk of the primary outcome. CONCLUSIONS: Multiple cardiorenal stress biomarkers are strongly prognostic in people with type 2 diabetes and albuminuria. Canagliflozin modestly reduced the longitudinal trajectory of rise in each biomarker. Change in the biomarker level in addition to the baseline level augments the primary outcome prediction. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02065791.
Pulmonary Vascular Differences in Eosinophilic Asthma after 2.5 Years of Anti–IL-5Rα Treatment
Authors: Marrissa J. McIntosh, Alexander M. Matheson, Harkiran K. Kooner, Rachel L. Eddy, Hana Serajeddini, Cory Yamashita, Grace Parraga
Journal: American Journal of Respiratory and Critical Care Medicine (2023)
Erratum. Remnant Cholesterol Is an Independent Predictor of Type 2 Diabetes: A Nationwide Population-Based Cohort Study. Diabetes Care 2023;46:305–312
Authors: Ji Hye Huh, Eun Roh, Seong Jin Lee, Sung-Hee Ihm, Kyung-Do Han, Jun Goo Kang
Journal: Diabetes Care (2023)
Metabolic reprogramming in Nrf2-driven proliferation of normal rat hepatocytes
Authors: Marta A. Kowalik, Keiko Taguchi, Marina Serra, Andrea Caddeo, Elisabetta Puliga, Marina Bacci, Seizo Koshiba, Jin Inoue, Eiji Hishinuma, Andrea Morandi, Silvia Giordano, Andrea Perra, Masayuki Yamamoto, Amedeo Columbano
Journal: Hepatology (2023)

Background and Aims: Cancer cells reprogram their metabolic pathways to support bioenergetic and biosynthetic needs and to maintain their redox balance. In several human tumors, the Keap1-Nrf2 system controls proliferation and metabolic reprogramming by regulating the pentose phosphate pathway (PPP). However, whether this metabolic reprogramming also occurs in normal proliferating cells is unclear. Approach and Results: To define the metabolic phenotype in normal proliferating hepatocytes, we induced cell proliferation in the liver by 3 distinct stimuli: liver regeneration by partial hepatectomy and hepatic hyperplasia induced by 2 direct mitogens: lead nitrate (LN) or triiodothyronine. Following LN treatment, well-established features of cancer metabolic reprogramming, including enhanced glycolysis, oxidative PPP, nucleic acid synthesis, NAD + /NADH synthesis, and altered amino acid content, as well as downregulated oxidative phosphorylation, occurred in normal proliferating hepatocytes displaying Nrf2 activation. Genetic deletion of Nrf2 blunted LN-induced PPP activation and suppressed hepatocyte proliferation. Moreover, Nrf2 activation and following metabolic reprogramming did not occur when hepatocyte proliferation was induced by partial hepatectomy or triiodothyronine. Conclusions: Many metabolic changes in cancer cells are shared by proliferating normal hepatocytes in response to a hostile environment. Nrf2 activation is essential for bridging metabolic changes with crucial components of cancer metabolic reprogramming, including the activation of oxidative PPP. Our study demonstrates that matured hepatocytes exposed to LN undergo cancer-like metabolic reprogramming and offers a rapid and useful in vivo model to study the molecular alterations underpinning the differences/similarities of metabolic changes in normal and neoplastic hepatocytes.
Deep learning based phenotyping of medical images improves power for gene discovery of complex disease
Authors: Brianna I. Flynn, Emily M. Javan, Eugenia Lin, Zoe Trutner, Karl Koenig, Kenoma O. Anighoro, Eucharist Kun, Alaukik Gupta, Tarjinder Singh, Prakash Jayakumar, Vagheesh M. Narasimhan
Journal: npj Digital Medicine (2023)

Abstract Electronic health records are often incomplete, reducing the power of genetic association studies. For some diseases, such as knee osteoarthritis where the routine course of diagnosis involves an X-ray, image-based phenotyping offers an alternate and unbiased way to ascertain disease cases. We investigated this by training a deep-learning model to ascertain knee osteoarthritis cases from knee DXA scans that achieved clinician-level performance. Using our model, we identified 1931 (178%) more cases than currently diagnosed in the health record. Individuals diagnosed as cases by our model had higher rates of self-reported knee pain, for longer durations and with increased severity compared to control individuals. We trained another deep-learning model to measure the knee joint space width, a quantitative phenotype linked to knee osteoarthritis severity. In performing genetic association analysis, we found that use of a quantitative measure improved the number of genome-wide significant loci we discovered by an order of magnitude compared with our binary model of cases and controls despite the two phenotypes being highly genetically correlated. In addition we discovered associations between our quantitative measure of knee osteoarthritis and increased risk of adult fractures- a leading cause of injury-related death in older individuals-, illustrating the capability of image-based phenotyping to reveal epidemiological associations not captured in the electronic health record. For diseases with radiographic diagnosis, our results demonstrate the potential for using deep learning to phenotype at biobank scale, improving power for both genetic and epidemiological association analysis.
Global epidemiologic patterns of oropharyngeal cancer incidence trends
Authors: Zachary S Zumsteg, Michael Luu, Philip S Rosenberg, Julia K Elrod, Freddie Bray, Salvatore Vaccarella, Christopher Gay, Diana J Lu, Michelle M Chen, Anil K Chaturvedi, Marc T Goodman
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background The emergence of human papillomavirus (HPV)–positive oropharyngeal cancer and evolving tobacco use patterns have changed the landscape of head and neck cancer epidemiology internationally. We investigated updated trends in oropharyngeal cancer incidence worldwide. Methods We analyzed cancer incidence data between 1993 and 2012 from 42 countries using the Cancer Incidence in Five Continents database volumes V through XI. Trends in oropharyngeal cancer incidence were compared with oral cavity cancers and lung squamous cell carcinomas using log-linear regression and age period–cohort modeling. Results In total, 156 567 oropharyngeal cancer, 146 693 oral cavity cancer, and 621 947 lung squamous cell carcinoma patients were included. Oropharyngeal cancer incidence increased (P &amp;lt; .05) in 19 and 23 countries in men and women, respectively. In countries with increasing male oropharyngeal cancer incidence, all but 1 had statistically significant decreases in lung squamous cell carcinoma incidence, and all but 2 had decreasing or nonsignificant net drifts for oral cavity cancer. Increased oropharyngeal cancer incidence was observed both in middle-aged (40-59 years) and older (≥60 years) male cohorts, with strong nonlinear birth cohort effects. In 20 countries where oropharyngeal cancer incidence increased for women and age period–cohort analysis was possible, 13 had negative or nonsignificant lung squamous cell carcinoma net drifts, including 4 countries with higher oropharyngeal cancer net drifts vs both lung squamous cell carcinoma and oral cavity cancer (P &amp;lt; .05 for all comparisons). Conclusions Increasing oropharyngeal cancer incidence is seen among an expanding array of countries worldwide. In men, increased oropharyngeal cancer is extending to older age groups, likely driven by human papillomavirus–related birth cohort effects. In women, more diverse patterns were observed, suggesting a complex interplay of risks factors varying by country, including several countries where female oropharyngeal cancer increases may be driven by HPV.
C5a-C5aR1 induces endoplasmic reticulum stress to accelerate vascular calcification <i>via</i> PERK-eIF2α-ATF4-CREB3L1 pathway
Authors: Aiting Liu, Zhenwei Chen, Xiaoxue Li, Chen Xie, Yanlian Chen, Xiaoyan Su, Ying Chen, Mengbi Zhang, Jie Chen, Tiecheng Yang, Jiangang Shen, Hui Huang
Journal: Cardiovascular Research (2023)

Vascular calcification (VC) predicts the morbidity and mortality in cardiovascular diseases. Vascular smooth muscle cells (VSMCs) osteogenic transdifferentiation is the crucial pathological basis for VC. To date, the molecular pathogenesis is still largely unclear. Notably, C5a-C5aR1 contributes to the development of cardiovascular diseases, and its closely related to physiological bone mineralization which is similar to VSMCs osteogenic transdifferentiation. However, the role and underlying mechanisms of C5a-C5aR1 in VC remain unexplored.
Five-year follow-up of phase II trial of stromal cells for bronchopulmonary dysplasia
Authors: So Yoon Ahn, Yun Sil Chang, Myung Hee Lee, Sein Sung, Ai-Rhan Kim, Won Soon Park
Journal: Thorax (2023)

Background We previously performed a phase II randomised double-blind clinical trial of mesenchymal stromal cell (MSCs) transplantation to prevent bronchopulmonary dysplasia in extremely premature infants. Subsequently, we followed the infants enrolled in this clinical trial to determine the safety and effectiveness of MSCs against bronchopulmonary dysplasia at 5-year follow-up. Methods We evaluated infants at 5 years of age receiving placebo or MSCs in a prospective follow-up study. Results In terms of the primary end point of composite respiratory morbidities, including respiratory problem-related readmission, emergency department visits or oxygen therapy, the MSC group had a rate of 60.7% for composite morbidities, while the control group showed a tendency of higher rate of 83.9% for the same outcomes without statistical significance. In terms of the secondary outcomes, the MSC group infants showed a tendency of being less likely to visit emergency department (control 67.7% vs MSC 35.7%) and to receive oxygen therapy (control 29.0% vs MSC 3.6%). No difference was observed in the incidence of respiratory problem-related hospital readmission or wheezing episodes between the groups. Conclusion Intratracheally instilled MSCs showed the possibility of potential to decrease respiratory symptom-related emergency department visits and oxygen therapy episodes in infants born extremely preterm during the 5 years after a phase II randomised controlled, double-blind trial of MSCs transplantation for bronchopulmonary dysplasia. This small size study suggests preliminary insights that can be further tested using larger sample sizes. Trial registration number NCT01897987 .
Resident cutaneous memory T cells: a clinical review of their role in chronic inflammatory dermatoses and potential as therapeutic targets
Authors: James P Pham, Kirsty J L Wark, Jane Woods, John W Frew
Journal: British Journal of Dermatology (2023)

Abstract Resident memory T cells (T-RMs) remain in epithelial barrier tissues after antigen exposure and the initial effector phase. These T-RMs provide effective antimicrobial and anticancer immunity; however, pathogenic T-RMs have been shown to mediate various chronic inflammatory disorders in a variety of tissue types. In the skin, T-RMs are referred to as resident cutaneous memory T cells (cT-RMs). Understanding the mechanisms leading to the development and establishment of these cT-RMs populations may allow for targeted treatments that provide durable responses in chronic immune-mediated skin diseases, even after cessation. In this review, we summarize the evidence on cT-RMs as drivers of chronic inflammatory dermatoses, including psoriasis, vitiligo, atopic dermatitis, cutaneous lupus erythematosus and alopecia areata, among others. Data from in vitro, animal model and ex vivo human studies are presented, with a focus on the potential for cT-RMs to trigger acute disease flares, as well as recurrent disease, by establishing an immune ‘memory’ in the skin. Furthermore, the available data on the potential for existing and novel treatments to affect the development or survival of cT-RMs in the skin are synthesized. The data suggest a dynamic and rapidly growing area in the field of dermatology; however, we also discuss areas in need of greater research to allow for optimal treatment selection for long-term disease control.
Erratum. The Incidence of Adult-Onset Type 1 Diabetes: A Systematic Review From 32 Countries and Regions. Diabetes Care 2022;45:994–1006
Authors: Jessica L. Harding, Pandora L. Wander, Xinge Zhang, Xia Li, Suvi Karuranga, Hongzhi Chen, Hong Sun, Yuting Xie, Richard A. Oram, Dianna J. Magliano, Zhiguang Zhou, Alicia J. Jenkins, Ronald C.W. Ma
Journal: Diabetes Care (2023)
Monitoring of Myocardial Involvement in Early Arrhythmogenic Right Ventricular Cardiomyopathy Across the Age Spectrum
Authors: Feddo P. Kirkels, Nick van Osta, Christine Rootwelt-Norberg, Monica Chivulescu, Tim van Loon, Eivind W. Aabel, Anna I. Castrini, Øyvind H. Lie, Folkert W. Asselbergs, Tammo Delhaas, Maarten J. Cramer, Arco J. Teske, Kristina H. Haugaa, Joost Lumens
Journal: Journal of the American College of Cardiology (2023)

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by fibrofatty replacement of primarily the right ventricular myocardium, a substrate for life-threatening ventricular arrhythmias (VAs). Repeated cardiac imaging of at-risk relatives is important for early disease detection. However, it is not known whether screening should be age-tailored. The goal of this study was to assess the need for age-tailoring of follow-up protocols in early ARVC by evaluating myocardial disease progression in different age groups. We divided patients with early-stage ARVC and genotype-positive relatives without overt structural disease and VA at first evaluation into 3 groups: age <30 years, 30 to 50 years, and ≥50 years. Longitudinal biventricular deformation characteristics were used to monitor disease progression. To link deformation abnormalities to underlying myocardial disease substrates, Digital Twins were created using an imaging-based computational modeling framework. We included 313 echocardiographic assessments from 82 subjects (57% female, age 39 ± 17 years, 10% probands) during 6.7 ± 3.3 years of follow-up. Left ventricular global longitudinal strain slightly deteriorated similarly in all age groups (0.1%-point per year [95% CI: 0.05-0.15]). Disease progression in all age groups was more pronounced in the right ventricular lateral wall, expressed by worsening in longitudinal strain (0.6%-point per year [95% CI: 0.46-0.70]) and local differences in myocardial contractility, compliance, and activation delay in the Digital Twin. Six patients experienced VA during follow-up. Disease progression was similar in all age groups, and sustained VA also occurred in patients aged >50 years without overt ARVC phenotype at first evaluation. Unlike recommended by current guidelines, our study suggests that follow-up of ARVC patients and relatives should not stop at older age.